Neosartorya fischeri antifungal protein 2 (NFAP2) selectively targets early Candida morphotypes, revealing transient susceptibility windows.

The escalating crisis of drug-resistant Candida species necessitates innovative antifungal strategies beyond traditional growth inhibition. Current treatments often face limitations due to evolving resistance mechanisms and a narrow therapeutic window, highlighting an urgent need to identify novel fungal vulnerabilities. This study explores the potential of targeting specific morphogenetic states of Candida, which are critical for virulence and host colonization, as a novel entry point for antifungal intervention. Understanding these transient developmental stages could unlock new therapeutic avenues that exploit unique physiological weaknesses in fungal pathogens.

Researchers investigated the antifungal activity of Neosartorya fischeri antifungal protein 2 (NFAP2) against Candida albicans and Candidozyma auris. They performed in vitro assays to identify morphotype-specific susceptibility during filament and pseudohypha formation. Integrated transcriptomic and network analyses were conducted on C. albicans to characterize gene expression signatures associated with NFAP2 sensitivity. For in vivo validation, they utilized the Galleria mellonella (wax moth larvae) infection model to assess NFAP2's impact on survival in both C. albicans and C. auris infections, comparing outcomes across different fungal morphotypes.

NFAP2 demonstrated selective targeting of early morphogenetic states in both C. albicans and C. auris, revealing a transient window of susceptibility during filament and pseudohypha formation. In C. albicans, increased susceptibility of emerging hyphae was associated with an anabolic, translation-associated gene expression signature, accompanied by suppression of stress-protective pathways. Conversely, C. auris pseudohyphal cells showed increased susceptibility without overt transcriptional remodeling, suggesting that NFAP2 sensitivity in this species is governed primarily by biophysical and post-transcriptional mechanisms. Importantly, in vitro morphotype-specific vulnerabilities translated to distinct in vivo outcomes in Galleria mellonella. > NFAP2 provided a moderate, transient survival benefit in pseudohyphal C. auris infections, indicating a therapeutic potential in this context. However, in filamentous C. albicans infections, a worsened outcome was observed, underscoring species- and morphotype-dependent activity. These findings collectively suggest that early morphogenetic states of Candida represent stress-sensitive phenotypes with heightened susceptibility to NFAP2.